Phthalates and substitute plasticizers: Main achievements from the European human biomonitoring initiative HBM4EU.

Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to answer policy-relevant questions and safeguard an efficient science-to-policy transfer of results. Human internal exposure levels were assessed using two data sets from all European regions and Israel. The first collated existing human biomonitoring (HBM) data (2005-2019).

Kisspeptin as potential biomarker of environmental chemical mixture effect on reproductive hormone profile: A pilot study in adolescent males.

Background: Kisspeptin has been proposed as an effect biomarker to understand the mechanisms by which some environmental chemicals adversely affect the human reproductive system.

Objective: To ascertain whether kisspeptin serum protein and DNA methylation levels are associated with exposure to several environmental chemicals (individually and as a mixture) and serum reproductive hormone levels in adolescent males.

Methods: Three phenols (bisphenol A [BPA], methyl-paraben [MPB], and benzophenone-3 [BP3]); two toxic metals (arsenic and cadmium); and four metabolites of non-persistent pesticides, including insecticides (2-isopropyl-6-methyl-4-pyrimidinol [IMPy], malathion diacid [MDA], and dimethylcyclopropane carboxylic acid [DCCA]) and fungicides (ethylene thiourea [ETU]) were measured in first-morning urine samples of 133 adolescent males aged 15-17 years from the INMA-Granada cohort.

Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations.

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies.

Concurrent Assessment of Phthalates/HEXAMOLL DINCH Exposure and Wechsler Intelligence Scale for Children Performance in Three European Cohorts of the HBM4EU Aligned Studies.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate/HEXAMOLL DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia.

Assessment of drinking water safety in the Netherlands using nationwide exposure and mortality data.

Background: Although drinking water in the Netherlands is generally accepted as safe, public concern about health risks of long-term intake still exist.

Objective: The aim was to explore associations between drinking water quality for nitrate, water hardness, calcium and magnesium and causes-of-death as related to cardiovascular diseases amongst which coronary heart disease and colorectal cancer.

Methods: We used national administrative databases on cause-specific mortality, personal characteristics, residential history, social economic indicators, air quality and drinking water quality for parameters specified by the EU Drinking Water Directive.

Comparing conventional and green fracturing fluids by chemical characterisation and effect-based screening.

There is public and scientific concern about air, soil and water contamination and possible adverse environmental and human health effects as a result of hydraulic fracturing activities. The use of greener chemicals in fracturing fluid aims to mitigate these effects. This study compares fracturing fluids marketed as either 'conventional' or 'green', as assessed by their chemical composition and their toxicity in bioassays.

Arsenic reduction to <1 µg/L in Dutch drinking water.

Arsenic (As) is a highly toxic element which naturally occurs in drinking water. In spite of substantial evidence on the association between many illnesses and chronic consumption of As, there is still a considerable uncertainty about the health risks due to low As concentrations in drinking water. In the Netherlands, drinking water companies aim to supply water with As concentration of <1 μg/L - a water quality goal which is tenfold more stringent than the current WHO guideline.

Chemical and bioassay assessment of waters related to hydraulic fracturing at a tight gas production site.

Publicly available chemical assessments of hydraulic fracturing related waters are generally based on shale gas practices in the U.S. There is a lack of information on hydraulic fracturing related gas development from EU countries and more generally on other types of extractions.

A strategy to validate a selection of human effect biomarkers using adverse outcome pathways: Proof of concept for phthalates and reproductive effects.

Human biomonitoring measures the concentrations of environmental chemicals or their metabolites in body fluids or tissues. Complementing exposure biomarkers with mechanistically based effect biomarkers may further elucidate causal pathways between chemical exposure and adverse health outcomes. We combined information on effect biomarkers previously implemented in human observational studies with mechanisms of action reported in experimental studies and with information from published Adverse Outcome Pathways (AOPs), focusing on adverse reproductive effects of phthalate exposure.

Prioritizing anthropogenic chemicals in drinking water and sources through combined use of mass spectrometry and ToxCast toxicity data.

Advancements in high-resolution mass spectrometry based methods have enabled a shift from pure target analysis to target, suspect and non-target screening analyses to detect chemicals in water samples. The multitude of suspect chemicals thereby detected needs to be prioritized for further identification, prior to health risk assessment and potential inclusion into monitoring programs. Here, we compare prioritization of chemicals in Dutch water samples based on relative intensities only to prioritization including hazard information based on high-throughput in vitro toxicity data.

Risk-based approach in the revised European Union drinking water legislation: Opportunities for bioanalytical tools.

A plethora of in vitro bioassays are developed in the context of chemical risk assessment and clinical diagnostics to test effects on different biological processes. Such assays can also be implemented in effect-based monitoring (EBM) of (drinking) water quality alongside chemical analyses. Effects-based monitoring can provide insight into risks for the environment and human health associated with exposure to (unknown) complex, low-level mixtures of micropollutants, which fits in the risk-based approach that was recently introduced in the European Drinking Water Directive.

Exploration of ToxCast/Tox21 bioassays as candidate bioanalytical tools for measuring groups of chemicals in water.

The present study explores the ToxCast/Tox21 database to select candidate bioassays as bioanalytical tools for measuring groups of chemicals in water. To this aim, the ToxCast/Tox21 database was explored for bioassays that detect polycyclic aromatic hydrocarbons (PAHs), aromatic amines (AAs), (chloro)phenols ((C)Ps) and halogenated aliphatic hydrocarbons (HAliHs), which are included in the European and/or Dutch Drinking Water Directives. Based on the analysis of the availability and performance of bioassays included in the database, we concluded that several bioassays are suitable as bioanalytical tools for assessing the presence of PAHs and (C)Ps in drinking water sources.

Toxicological risk assessment and prioritization of drinking water relevant contaminants of emerging concern.

Toxicological risk assessment of contaminants of emerging concern (CEC) in (sources of) drinking water is required to identify potential health risks and prioritize chemicals for abatement or monitoring. In such assessments, concentrations of chemicals in drinking water or sources are compared to either (i) health-based (statutory) drinking water guideline values, (ii) provisional guideline values based on recent toxicity data in absence of drinking water guidelines, or (iii) generic drinking water target values in absence of toxicity data. Here, we performed a toxicological risk assessment for 163 CEC that were selected as relevant for drinking water.

Tracing nitrogenous disinfection byproducts after medium pressure UV water treatment by stable isotope labeling and high resolution mass spectrometry.

Advanced oxidation processes are important barriers for organic micropollutants (e.g., pharmaceuticals, pesticides) in (drinking) water treatment.

Influence of process conditions and water quality on the formation of mutagenic byproducts in UV/H2O2 processes.

UV/H2O2 processes in drinking water treatment may generate byproducts which cause an increased response in Ames fluctuation assays. As this probably involves a mixture of substances in very low concentrations, it is challenging to identify the individual byproducts. Therefore it was studied under which conditions mutagenic byproducts are formed and how this can be prevented.

Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds.

Many chemicals can induce allergic contact dermatitis. Because evaluation of skin sensitizing potential by animal testing is prohibited for cosmetics, and screening of many chemicals is required within Registration, Evaluation, Authorisation and Restriction of Chemicals, urgent need exists for predictive in vitro assays to identify contact allergens. Keratinocytes (KC) are the first cells encountered when chemicals land on the skin.

Gene expression changes in the mesenteric lymph nodes of rats after oral peanut extract exposure.

New techniques are needed to broaden the understanding of the food allergic response. The capacity of peanut extract to influence gene expression profiles was investigated in a Brown Norway rat model for food allergy. Brown Norway rats were sensitized to peanut extract (0, 1 and 10 mg/rat/d) by daily oral gavage and were dissected after 3, 7 or 14 days of exposure.

Gene expression profiling of Bis(tri-n-butyltin)oxide (TBTO)-induced immunotoxicity in mice and rats.

Bis(tri-n-butyltin)oxide (TBTO) is one of the organotin compounds that have been used as biocides and occur as persistent environmental pollutants. Human exposure to these compounds occurs through consumption of meat and fish products in which they accumulate. The most sensitive endpoint of TBTO exposure is immunotoxicity.

Overlapping gene expression profiles of model compounds provide opportunities for immunotoxicity screening.

In order to investigate immunotoxic effects of a set of model compounds in mice, a toxicogenomics approach was combined with information on macroscopical and histopathological effects on spleens and on modulation of immune function. Bis(tri-n-butyltin)oxide (TBTO), cyclosporin A (CsA), and benzo[a]pyrene (B[a]P) were administered to C57BL/6 mice at immunosuppressive dose levels. Acetaminophen (APAP) was included in the study since indications of immunomodulating properties of this compound have appeared in the literature.

In vitro immunotoxicity of bis(tri-n-butyltin)oxide (TBTO) studied by toxicogenomics.

The biocide and environmental pollutant bis(tri-n-butyltin)oxide (TBTO) causes thymus atrophy in rodents. Whether the depletion of thymic lymphocytes by tributyltin compounds may be the result of inhibition of cell proliferation or induction of apoptosis is subject of debate. We examined gene expression profiles in primary rat thymocytes exposed to TBTO in vitro at dose levels of 0, 0.

Toxicogenomics in the assessment of immunotoxicity.

Microarray analysis is used for simultaneous measurement of expression of thousands of genes in a given sample and as such extends and deepens our understanding of biological processes. Application of the technique in toxicology is referred to as toxicogenomics. The examples of assessment of immunotoxicity by gene expression profiling presented and discussed here, show that microarray analysis is able to detect known and novel effects of a wide range of immunomodulating agents.